The Experts below are selected from a list of 207 Experts worldwide ranked by ideXlab platform
Kristof Chwalisz - One of the best experts on this subject based on the ideXlab platform.
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selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis
Endocrine Reviews, 2005Co-Authors: Kristof Chwalisz, Deborah A Demanno, Gerd Schubert, Craig A Winkel, Maria Pérez, Walter ElgerAbstract:Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands. SPRMs exert clinically relevant tissue-selective progesterone agonist, antagonist, or mixed agonist/antagonist effects on various progesterone target tissues in vivo. Asoprisnil (J867) is the first SPRM to reach an advanced stage of clinical development for the treatment of symptomatic uterine fibroids and endometriosis. Asoprisnil belongs to the class of 11β-benzaldoxime-substituted estratrienes that exhibit partial progesterone agonist/antagonist effects with high progesterone receptor specificity in animals and humans. Asoprisnil has no antiglucocorticoid activity in humans at therapeutic doses. It exhibits endometrial antiproliferative effects on the endometrium and breast in primates. Unlike progesterone antagonists, asoprisnil does not induce labor in relevant models of pregnancy and parturition. It induces amenorrhea primarily by targeting the endometrium. In human subjects with uterine fibroi...
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Therapeutic potential for the selective progesterone receptor modulator asoprisnil in the treatment of leiomyomata.
Seminars in Reproductive Medicine, 2004Co-Authors: Kristof Chwalisz, Deborah A Demanno, Ramesh Garg, Lois Larsen, Cynthia Mattia-goldberg, Therese SticklerAbstract:Asoprisnil is a novel selective progesterone receptor modulator that exhibits partial agonist and antagonist activities in animals and humans. It demonstrates a high degree of progesterone receptor specificity and tissue selectivity. Although asoprisnil at high doses exhibited some antiglucocorticoid activity in animal models, no antiglucocorticoid effects were observed at therapeutic doses in humans. In male rats, asoprisnil showed mixed androgenic and antiandrogenic properties. Unlike antiprogestins, asoprisnil at high doses exhibited only marginal labor-inducing activity in guinea pigs during midpregnancy and was completely ineffective in inducing preterm parturition. In nonhuman primates, asoprisnil completely eliminated menstrual cyclicity and induced endometrial atrophy. Early clinical studies of asoprisnil in healthy volunteers demonstrated a dose-dependent suppression of menstruation, irrespective of the effects on ovulation, with no change in basal estrogen concentrations and no breakthrough bleeding. Phase 2 studies in subjects with uterine fibroids demonstrated that asoprisnil induced amenorrhea and reduced the volume of the dominant leiomyoma in a dose-dependent manner without altered basal estrogen and with virtually no clinical symptoms of estrogen deprivation. Asoprisnil seems to exhibit a direct inhibitory effect on both the endometrium and leiomyoma. In all studies to date, asoprisnil has maintained a favorable safety and tolerability profile. Thus, asoprisnil has the potential to target the major clinical symptoms of leiomyomata related to both menorrhagia and the size of the tumors and may, therefore, reduce or eliminate the need for surgery.
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asoprisnil j867 a selective progesterone receptor modulator for gynecological therapy
Steroids, 2003Co-Authors: Deborah A Demanno, Gerd Schubert, Walter Elger, Ramesh Garg, Ronald Lee, Birgitt Schneider, Holger Hessstumpp, Kristof ChwaliszAbstract:Asoprisnil is a novel selective steroid receptor modulator that shows unique pharmacodynamic effects in animal models and humans. Asoprisnil, its major metabolite J912, and structurally related compounds represent a new class of progesterone receptor (PR) ligands that exhibit partial agonist and antagonist activities in vivo. Asoprisnil demonstrates a high degree of receptor and tissue selectivity, with high-binding affinity for PR, moderate affinity for glucocorticoid receptor (GR), low affinity for androgen receptor (AR), and no binding affinity for estrogen or mineralocorticoid receptors. In the rabbit endometrium, both asoprisnil and J912 induce partial agonist and antagonist effects. Asoprisnil induces mucification of the guinea pig vagina and has pronounced anti-uterotrophic effects in normal and ovariectomized guinea pigs. Unlike antiprogestins, asoprisnil shows only marginal labor-inducing activity during mid-pregnancy and is completely ineffective in inducing preterm parturition in the guinea pig. Asoprisnil exhibits only marginal antiglucocorticoid activity in transactivation in vitro assays and animal models. In male rats, asoprisnil showed weak androgenic and anti-androgenic properties. In toxicological studies in female cynomolgus monkeys, asoprisnil treatment abolished menstrual cyclicity and endometrial atrophy. Early clinical studies of asoprisnil in normal volunteers demonstrated a dose-dependent suppression of menstruation irrespective of the effects on ovulation, with no change in basal estrogen concentrations and no antiglucocorticoid effects. Unlike progestins, asoprisnil does not induce breakthrough bleeding. With favorable safety and tolerability profiles thus far, asoprisnil appears promising as a novel treatment of gynecological disorders, such as uterine fibroids and endometriosis.
Deborah A Demanno - One of the best experts on this subject based on the ideXlab platform.
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selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis
Endocrine Reviews, 2005Co-Authors: Kristof Chwalisz, Deborah A Demanno, Gerd Schubert, Craig A Winkel, Maria Pérez, Walter ElgerAbstract:Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands. SPRMs exert clinically relevant tissue-selective progesterone agonist, antagonist, or mixed agonist/antagonist effects on various progesterone target tissues in vivo. Asoprisnil (J867) is the first SPRM to reach an advanced stage of clinical development for the treatment of symptomatic uterine fibroids and endometriosis. Asoprisnil belongs to the class of 11β-benzaldoxime-substituted estratrienes that exhibit partial progesterone agonist/antagonist effects with high progesterone receptor specificity in animals and humans. Asoprisnil has no antiglucocorticoid activity in humans at therapeutic doses. It exhibits endometrial antiproliferative effects on the endometrium and breast in primates. Unlike progesterone antagonists, asoprisnil does not induce labor in relevant models of pregnancy and parturition. It induces amenorrhea primarily by targeting the endometrium. In human subjects with uterine fibroi...
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Therapeutic potential for the selective progesterone receptor modulator asoprisnil in the treatment of leiomyomata.
Seminars in Reproductive Medicine, 2004Co-Authors: Kristof Chwalisz, Deborah A Demanno, Ramesh Garg, Lois Larsen, Cynthia Mattia-goldberg, Therese SticklerAbstract:Asoprisnil is a novel selective progesterone receptor modulator that exhibits partial agonist and antagonist activities in animals and humans. It demonstrates a high degree of progesterone receptor specificity and tissue selectivity. Although asoprisnil at high doses exhibited some antiglucocorticoid activity in animal models, no antiglucocorticoid effects were observed at therapeutic doses in humans. In male rats, asoprisnil showed mixed androgenic and antiandrogenic properties. Unlike antiprogestins, asoprisnil at high doses exhibited only marginal labor-inducing activity in guinea pigs during midpregnancy and was completely ineffective in inducing preterm parturition. In nonhuman primates, asoprisnil completely eliminated menstrual cyclicity and induced endometrial atrophy. Early clinical studies of asoprisnil in healthy volunteers demonstrated a dose-dependent suppression of menstruation, irrespective of the effects on ovulation, with no change in basal estrogen concentrations and no breakthrough bleeding. Phase 2 studies in subjects with uterine fibroids demonstrated that asoprisnil induced amenorrhea and reduced the volume of the dominant leiomyoma in a dose-dependent manner without altered basal estrogen and with virtually no clinical symptoms of estrogen deprivation. Asoprisnil seems to exhibit a direct inhibitory effect on both the endometrium and leiomyoma. In all studies to date, asoprisnil has maintained a favorable safety and tolerability profile. Thus, asoprisnil has the potential to target the major clinical symptoms of leiomyomata related to both menorrhagia and the size of the tumors and may, therefore, reduce or eliminate the need for surgery.
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asoprisnil j867 a selective progesterone receptor modulator for gynecological therapy
Steroids, 2003Co-Authors: Deborah A Demanno, Gerd Schubert, Walter Elger, Ramesh Garg, Ronald Lee, Birgitt Schneider, Holger Hessstumpp, Kristof ChwaliszAbstract:Asoprisnil is a novel selective steroid receptor modulator that shows unique pharmacodynamic effects in animal models and humans. Asoprisnil, its major metabolite J912, and structurally related compounds represent a new class of progesterone receptor (PR) ligands that exhibit partial agonist and antagonist activities in vivo. Asoprisnil demonstrates a high degree of receptor and tissue selectivity, with high-binding affinity for PR, moderate affinity for glucocorticoid receptor (GR), low affinity for androgen receptor (AR), and no binding affinity for estrogen or mineralocorticoid receptors. In the rabbit endometrium, both asoprisnil and J912 induce partial agonist and antagonist effects. Asoprisnil induces mucification of the guinea pig vagina and has pronounced anti-uterotrophic effects in normal and ovariectomized guinea pigs. Unlike antiprogestins, asoprisnil shows only marginal labor-inducing activity during mid-pregnancy and is completely ineffective in inducing preterm parturition in the guinea pig. Asoprisnil exhibits only marginal antiglucocorticoid activity in transactivation in vitro assays and animal models. In male rats, asoprisnil showed weak androgenic and anti-androgenic properties. In toxicological studies in female cynomolgus monkeys, asoprisnil treatment abolished menstrual cyclicity and endometrial atrophy. Early clinical studies of asoprisnil in normal volunteers demonstrated a dose-dependent suppression of menstruation irrespective of the effects on ovulation, with no change in basal estrogen concentrations and no antiglucocorticoid effects. Unlike progestins, asoprisnil does not induce breakthrough bleeding. With favorable safety and tolerability profiles thus far, asoprisnil appears promising as a novel treatment of gynecological disorders, such as uterine fibroids and endometriosis.
Walter Elger - One of the best experts on this subject based on the ideXlab platform.
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selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis
Endocrine Reviews, 2005Co-Authors: Kristof Chwalisz, Deborah A Demanno, Gerd Schubert, Craig A Winkel, Maria Pérez, Walter ElgerAbstract:Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands. SPRMs exert clinically relevant tissue-selective progesterone agonist, antagonist, or mixed agonist/antagonist effects on various progesterone target tissues in vivo. Asoprisnil (J867) is the first SPRM to reach an advanced stage of clinical development for the treatment of symptomatic uterine fibroids and endometriosis. Asoprisnil belongs to the class of 11β-benzaldoxime-substituted estratrienes that exhibit partial progesterone agonist/antagonist effects with high progesterone receptor specificity in animals and humans. Asoprisnil has no antiglucocorticoid activity in humans at therapeutic doses. It exhibits endometrial antiproliferative effects on the endometrium and breast in primates. Unlike progesterone antagonists, asoprisnil does not induce labor in relevant models of pregnancy and parturition. It induces amenorrhea primarily by targeting the endometrium. In human subjects with uterine fibroi...
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asoprisnil j867 a selective progesterone receptor modulator for gynecological therapy
Steroids, 2003Co-Authors: Deborah A Demanno, Gerd Schubert, Walter Elger, Ramesh Garg, Ronald Lee, Birgitt Schneider, Holger Hessstumpp, Kristof ChwaliszAbstract:Asoprisnil is a novel selective steroid receptor modulator that shows unique pharmacodynamic effects in animal models and humans. Asoprisnil, its major metabolite J912, and structurally related compounds represent a new class of progesterone receptor (PR) ligands that exhibit partial agonist and antagonist activities in vivo. Asoprisnil demonstrates a high degree of receptor and tissue selectivity, with high-binding affinity for PR, moderate affinity for glucocorticoid receptor (GR), low affinity for androgen receptor (AR), and no binding affinity for estrogen or mineralocorticoid receptors. In the rabbit endometrium, both asoprisnil and J912 induce partial agonist and antagonist effects. Asoprisnil induces mucification of the guinea pig vagina and has pronounced anti-uterotrophic effects in normal and ovariectomized guinea pigs. Unlike antiprogestins, asoprisnil shows only marginal labor-inducing activity during mid-pregnancy and is completely ineffective in inducing preterm parturition in the guinea pig. Asoprisnil exhibits only marginal antiglucocorticoid activity in transactivation in vitro assays and animal models. In male rats, asoprisnil showed weak androgenic and anti-androgenic properties. In toxicological studies in female cynomolgus monkeys, asoprisnil treatment abolished menstrual cyclicity and endometrial atrophy. Early clinical studies of asoprisnil in normal volunteers demonstrated a dose-dependent suppression of menstruation irrespective of the effects on ovulation, with no change in basal estrogen concentrations and no antiglucocorticoid effects. Unlike progestins, asoprisnil does not induce breakthrough bleeding. With favorable safety and tolerability profiles thus far, asoprisnil appears promising as a novel treatment of gynecological disorders, such as uterine fibroids and endometriosis.
Rainer Rupprecht - One of the best experts on this subject based on the ideXlab platform.
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Hypothalamic-pituitary-adrenocortical system dysregulation and new treatment strategies in depression.
Expert Review of Neurotherapeutics, 2009Co-Authors: Cornelius Schüle, Thomas C. Baghai, Daniela Eser, Rainer RupprechtAbstract:According to the corticoid receptor hypothesis of depression, hyperactivity of the hypothalamic–pituitary–adrenocortical (HPA) system is one of the major pathophysiological factors for the development of depression and opens a broad range of new antidepressant treatment options that are related to direct interventions in HPA system regulation in depressed patients. These new therapy strategies include inhibition of hypothalamic corticotropin-releasing hormone (CRH) release, antagonism at CRH1 receptors, antagonism at vasopressin V1b receptors, inhibition of cortisol synthesis, antiglucocorticoid treatment with dehydroepiandrosterone and treatment with glucocorticoid receptor antagonists. Although preclinical data support the view that CRH1 receptor antagonists are useful in the treatment of depression, currently no controlled studies are available that demonstrate clinical efficacy in depressed patients. The use of the antiglucocorticoid neuroactive steroid dehydroepiandrosterone, the cortisol synthesis i...
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Hypothalamic-pituitary-adrenocortical system dysregulation and new treatment strategies in depression.
Expert review of neurotherapeutics, 2009Co-Authors: Cornelius Schüle, Thomas C. Baghai, Daniela Eser, Rainer RupprechtAbstract:According to the corticoid receptor hypothesis of depression, hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system is one of the major pathophysiological factors for the development of depression and opens a broad range of new antidepressant treatment options that are related to direct interventions in HPA system regulation in depressed patients. These new therapy strategies include inhibition of hypothalamic corticotropin-releasing hormone (CRH) release, antagonism at CRH1 receptors, antagonism at vasopressin V1b receptors, inhibition of cortisol synthesis, antiglucocorticoid treatment with dehydroepiandrosterone and treatment with glucocorticoid receptor antagonists. Although preclinical data support the view that CRH1 receptor antagonists are useful in the treatment of depression, currently no controlled studies are available that demonstrate clinical efficacy in depressed patients. The use of the antiglucocorticoid neuroactive steroid dehydroepiandrosterone, the cortisol synthesis inhibitor metyrapone and the glucocorticoid receptor antagonist mifepristone in depression has been demonstrated in some small, double-blind, placebo-controlled studies. However, three recently completed Phase III trials failed to significantly separate mifepristone from placebo in depression. Thus, it is unclear at present to what extent new, clinically effective antidepressant therapies can be developed based on the corticoid receptor hypothesis of depression.
Raymond A. Daynes - One of the best experts on this subject based on the ideXlab platform.
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Functions as More Than an Antiglucocorticoid in Preserving Immunocompetence after Thermal Injury
1995Co-Authors: Barbara A. Araneo, Raymond A. DaynesAbstract:(RU486), after the burn revealed no d&e&&e in immune function between the RU486-treated mice and the untreated burn group. At the levels of drug used, both DHEA and RU486 were able to completely block the effects of glucocorticoid treatment on immune function in mice, establishing a direct antiglucocorticoid activity of each steroid. Because thermal injury-mediated changes in immunity could be overcome by the administration of DHEA, but not RU486, the data suggest that the elevations in adrenal output of glucocorticoids are not responsible for the alterations in immune function after experimental thermal injury of mice. The results of this study have provided further insight into the mechanism of action of DHEA in this experimental model. The ability of DHEA to preserve immune function in severely thermally injured mice appears to extend beyond an antiglucocorticoid activity.
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Dehydroepiandrosterone functions as more than an antiglucocorticoid in preserving immunocompetence after thermal injury.
Endocrinology, 1995Co-Authors: Barbara A. Araneo, Raymond A. DaynesAbstract:Reduced cellular immune responses and altered cytokine production by cells from mice exposed to thermal injury are minimized if dehydroepiandrosterone (DHEA) is administered after experimental burn injury in mice. An analysis of similar tests of immune function developed by mice given the antiglucocorticoid, 17 beta-hydroxy-11 beta-[4-dimethylaminophenyl]17 alpha-propynyl-estra-4,5-diene-3-one (RU486), after the burn revealed no difference in immune function between the RU486-treated mice and the untreated burn group. At the levels of drug used, both DHEA and RU486 were able to completely block the effects of glucocorticoid treatment on immune function in mice, establishing a direct antiglucocorticoid activity of each steroid. Because thermal injury-mediated changes in immunity could be overcome by the administration of DHEA, but not RU486, the data suggest that the elevations in adrenal output of glucocorticoids are not responsible for the alterations in immune function after experimental thermal injury ...